Our laboratory discovered an important role for RNA binding proteins (RBPs) in the pathophysiology of tauopathy. Tau accumulates in the neuronal soma as part of a normal biological pathway involving the translational stress response, and formation of stress granules (SGs). The association of tau with SGs also stimulates tau aggregation, indicating that tau aggregation can occur normally as part of the translational stress response. Our recent studies demonstrate a key role for RNA binding proteins in tauopathy in vivo. We demonstrated that reducing levels of the RNA binding protein TIA1 (which nucleates SGs) significantly delays disease progression in the P301S tau mouse. Reducing the RBP TIA1 by half (TIA1+/-) yielded a 33% increase in lifespan, with rescue of synaptic loss, neuronal loss, reduced inflammation and behavioral rescue at 6 months. This strong neuroprotection occurs with a corresponding dramatic (90%) reduction in tau oligomerization. Analysis of the full TIA1 deletion revealed a surprise. The P301S TIA1-/- mice live longer and show behavioral rescue at 6-months, however, they also exhibit a major (>10-fold) increase in reactive microglia, suggesting a strong neuro- inflammatory response. We hypothesize that TIA1 removal in neurons inhibits neurodegeneration, while TIA1 removal from microglia enhances the neuro-inflammatory response. Two alternate scenarios might explain the presence of neuroprotection in the face of an enhanced neuro- inflammatory response. Scenario 1: The benefit accrued to neurons from TIA1 reduction is stronger than the harm resulting from the increased neuro-inflammation. Scenario 2: Loss of TIA1 in microglia produces a neuro-inflammation that is surprisingly beneficial. This proposal will produce conditional TIA1 knockout mice that lack TIA1 in either neurons or microglia, and test these scenarios. Aim 1: Generate conditional TIA1 knockouts (KO) with CRE driven by promoters selective for cholinergic neurons (ChAT), pyramidal neurons of the frontal cortex and hippocampus (CamKII), and microglia (Cx3cr1). Validate expression by immunohistochemistry. Aim 2: Determine how selective deletion of TIA1 from neurons or microglia modifies the neuroprotective and inflammatory phenotypes: We will use the microglial selective TIA1 KO mice to determine whether the enhanced inflammatory response exacerbates inflammation and neurodegeneration, using the facial nerve axotomy model. We will also examine the neuronal selective TIA1 KO mice to determine if protection is observed against a challenge with the axotomy model, as well as the glutamate analogue, kainic acid.